Ask the Experts: aducanumab

Written by Neuro Central
Drug development Neurodegeneration and degenerative disease Opinion
Ask the Experts: aducanumab

Aducanumab was approved for use by the US FDA in June 2021, a decision that caused much debate within the neuroscience community. To what extent has amyloid been shown to be a causative characteristic of Alzheimer’s? Does – and should – the ‘patient voice’ play a role in these kind of approval decisions? How may this approval impact future Alzheimer’s drug approvals? In this ‘Ask the Experts’ feature, we’ve brought together a panel of key thought leaders to discuss the Alzheimer’s drug aducanumab.

Our experts for this discussion include Robert Howard (University College London; UK), Mark Dallas (University of Reading; UK) and David Whitrap (Institute for Clinical and Economic Review; BS, USA).

Aducanumab questions:

Given that Alzheimer’s is believed to exist across a continuum and isn’t a single disease, could aducanumab provide clinical benefit to individuals across that entire spectrum?

Robert Howard (RH): The first and important thing to say is that the evidence from the 3268 participants in the EMERGE and ENGAGE trials showed that aducanumab failed to provide convincing clinical benefit to the MCI and mild AD population involved. It is even less likely to be effective in patients with more advanced AD. Whether removal of amyloid (which aducanumab is good at) is associated with delay of cognitive and functional decline at an even earlier stage – that of confirmed amyloid positivity but no measurable cognitive change – is theoretically appealing but not yet supported by any evidence.

Mark Dallas (MD): This is one of the challenges of developing new drugs for Alzheimer’s disease, I don’t think that one medicine will be able to provide benefit to everyone living with Alzheimer’s. In my opinion this was a mistake from the FDA to approve aducanumab for everyone living with Alzheimer’s disease, and I note that the FDA has now changed this guidance to focus on a specific group of people that took part in the trials (those living with milder forms of the disease).

David Whitrap (DW): At ICER, we always follow the data. In the case of aducanumab, there’s clear evidence that the therapy reduces amyloid plaque in the brain and there’s a hopeful hypothesis that this may translate to improving the lives of individuals with early disease. However, the clinical evidence remains unclear – and even contradictory – to determine if removing amyloid plaques actually slows memory loss. What we need is more data.

Before this decision, the Alzheimer’s research space seemed to be moving towards tau as a more stringent predictor of Alzheimer’s disease and the next target to focus on for therapeutics – where do you stand on the tau versus amyloid debate?

RH: I think it would be a mistake to think that these are the only important models in the search for AD treatments. They can only be said to be reflections of the neuropathological features of established AD. Their presence in the brains of people with AD may turn out to be nothing more than downstream epiphenomena of important earlier processes that may turn out to be fruitful treatment targets. The truth is, we just do not know at this stage. It is not good for the field for powerful establishment figures, who are often influential and control research resources, to dogmatically hold positions that could inhibit exploration of novel mechanisms.

MD: Focussing on single entities has progressed the research to date, but I think given the multifactorial nature of Alzheimer’s we should be focussing on global changes that are apparent.  I have previously been an advocate for amyloid but have now converted to a more all-inclusive approach to consider the factors driving the changing inflammatory status of our brains. There is a growing interest in brain inflammation and it acting as a driving force to initiate disease progression. This inflammation is seen across the spectrum and could provide both therapeutic and diagnostic opportunities independent of amyloid or tau.

DW: With how devastating this disease can be, there’s a moral imperative, as well as a financial incentive, for pharmaceutical companies to explore all approaches that may improve the lives of patients and caregivers.

That said, there’s a real risk that aducanumab’s accelerated approval may incentivize investment into follow-on amyloid-reducing therapies, which the US FDA may now feel compelled to approve regardless of those treatments’ abilities to demonstrate actual cognitive improvement, redirecting investment away from other investigational therapies that may ultimately be more effective for patients but would require more comprehensive clinical trials.

Central to the controversy regarding aducanumab is the decision to approve the drug based on its ability to reduce amyloid plaques, rather than a clear demonstration of its clinical benefit. To what extent has amyloid been shown to be a causative – rather than resultant – characteristic of Alzheimer’s?

RH: There is no evidence that reducing amyloid plaques leads to any clinical benefits. Indeed, there is plenty of evidence from multiple drug studies that reducing amyloid has little or no discernible effect on cognitive or functional decline. Many of us were very surprised that the FDA implied that there were reasons to believe that this could be the case. They were incorrect to say this.

MD: This is an area of current debate to which we do not yet have a definitive answer. In my opinion the evidence currently supports amyloid build up playing a causative role in the progression of Alzheimer’s. The challenge now is finding the window of opportunity to initiate treatment so that suppression of amyloid build up leads to real patient benefit.

Do you think it is possible that reducing plaques could be a purely cosmetic result; removing a produced physical characteristic of Alzheimer’s without addressing the root pathogenic mechanism of the disease?

RH: Not “possible”, I think the evidence shows it is almost a certainty.

MD: If we could prevent the plaques appearing in the first place that would be a game changer in terms of developing treatments for Alzheimer’s disease. The reduction of pre-existing plaques I think is only going to offer limited relief to those living with Alzheimer’s and will probably only be seen at an individual level rather than benefitting the whole Alzheimer’s community.

Some stakeholders argue that this surrogate endpoint (the reduction in amyloid plaques) is not very person-centered – what are some of the challenges and implications associated with using surrogate endpoints in clinical research and approval decisions?

RH: I think that if the link between amyloid levels and subsequent cognitive and functional decline that the FDA say they believe exists actually did, then it would have been very reasonable to use such a surrogate endpoint, rather than having to wait for several years to demonstrate a slowing of disease progression. I think that patients and their families understand this. Unfortunately, the evidence suggests that the hoped-for link does not exist.

DW: Follow the evidence. While validated surrogate endpoints can be predictive of meaningful clinical benefits, there’s no need to rely on surrogates in the case of aducanumab, where we have two Phase III studies that already measured the outcomes that patients actually care about.

Further, after so many other amyloid-reducing therapies have failed to show a meaningful clinical benefit, it’s reasonable that, if an anti-amyloid therapy is to be approved, it needs clinical data that can overcome amyloid skeptics.

We are at a point where drug sponsors can – and should – measure the outcomes that matter most to patients.

To what extent does – and should – the ‘patient voice’ play a role in these kinds of approval decisions?

RH: This is such a difficult question. Of course, the priorities of patients and their families should be paramount. However, when people are desperate and vulnerable to the effects of misinformation about potential efficacy and ultimate effectiveness, their decision-making needs to be viewed in this context.

If patient groups had been told the cold truth about aducanumab, i.e. that it probably does not have significant clinical efficacy and that reductions in amyloid load have not been shown to translate to clinical benefit in multiple previous studies, then the ‘patient voice’ might have been more valuable. Instead, they were told that the treatment slowed disease progression by 22%, improved function by 40% and impacted upon amyloid with a “reasonable consideration” that would improve clinical outcomes. Primed with such misinformation, I do not consider that patients were actually able to have useful or valid input into the approval process.

MD: I think those living with Alzheimer’s disease play an important role in setting the agenda for the need for new medicines. They understand more than anyone the suffering Alzheimer’s brings and the hope that a new medicine would bring. We have to be clear however that this voice does not cloud our judgement when it comes to medicine approval. The decision to approve should be based solely on the experimental and clinical evidence. The ‘patient voice’ can get a medicine to the door for approval but it should be the evidence presented that decides if it passes through or not.

DW: The patient voice always needs to be at the center of healthcare decision-making. At ICER, we heavily rely on patients to help us understand the burden of a disease and the outcomes that matter most.

Clearly, patients need transformative new treatments. But, they also want an FDA approval to guarantee that a drug is truly effective, they want new drugs to be priced affordably and they want insurers to reciprocate fair pricing with fair access. All of these priorities are important aspects of the patient voice.

The cost of the drug is believed to be high. How do you evaluate the cost–effectiveness of a therapy for which there are uncertain and contradictory data available? Could the cost of the drug exacerbate access disparities in dementia care?

RH: In the absence of clear efficacy, there can be no effectiveness. In the absence of effectiveness, there can be no cost-effectiveness.

DW: The evidence on aducanumab is complex, concerning and contradictory. ICER blended the results from the two Phase III pivotal trials to try to quantify the treatment’s potential benefit and, in doing so, we suggested that a fair price would be between USD$3000–8400 per year. We don’t necessarily believe that the average of the two trials represents aducanumab’s true benefit, but, we also have no reason to expect that the positive trial is more reliable than the negative trial.

What we really need is an additional clinical trial; if such a trial were required prior to approval, the results would be ready long before the 2030 due date the FDA established for the Phase IV confirmatory trial upon which the accelerated approval is conditioned. If policymakers ultimately believe that the negative pivotal trial is accurate, then there’s no price at which aducanumab would be cost effective.

Alzheimer’s disease disproportionately affects people of color, and our health system needs to ensure that any effective new treatment be priced and administered in a manner that reduces – or at least doesn’t exacerbate – existing health disparities. This concern would be incredibly important for a high-priced, highly effective treatment.

However, in the specific case of aducanumab – a high-priced treatment with insufficient evidence of benefit – there’s less concern about health disparities tied directly to who gets the treatment and who doesn’t. But, there’s a real concern about the overall budget impact of aducanumab across Medicare, Medicaid and other programs, and how these potentially high costs for aducanumab can ultimately redirect other resources away from under-served populations.

What kinds of post-approval data collection and analyses will be needed to maintain market access of aducanumab?

RH: There are no data collection or analysis scenarios, short of further randomised placebo-controlled trials, that can shed further light on this. The designs that I have heard are being considered for post-approval data collection will collect nothing more than safety data.

MD: First and foremost, it has to be shown to provide clinical benefit to those living with Alzheimer’s. This has not been done to date and the post approval trials to work this out are likely to drag on (while individuals may be taking the medicine) which in my view has no benefit to anyone.

DW: We need to see hard data around a slowing of cognitive decline among individuals with early disease. We’d like those data to sufficiently support the results of the positive Phase III trial (EMERGE) and sufficiently refute the results of the negative Phase III trial (ENGAGE).

How may this approval impact future Alzheimer’s drug approvals – with all the controversy, does it set a lower standard? Could this open up a role for real-world evidence in supplementing clinical trial data?

RH: It sets an unhelpfully low standard that will not convince physicians to prescribe (unless they are unrealistically optimistic or financially greedy). We should not soften the rigor with which we evaluate efficacy and effectiveness of potential dementia treatment and use of the accelerated approval pathway has set a damaging and unhelpful precedent. There can be no substitute for the conduct of conventional double-blind randomised controlled trials if we are to establish efficacy and safety of dementia treatments in the future.

MD: It does change the goal posts somewhat and could see some Alzheimer’s drugs (amyloid targeted) that failed previously come back around seeking approval. There will be an intense period of re-analysis of data to see if these drugs would be fit for the accelerated scheme and use of the surrogate endpoints. Without a clear demonstration of efficacy, medicines are being approved and entering the market which, as a scientist, erodes trust in the decision making processes.

DW: There’s a real risk that it has established a lower standard. If a future drug is able to show that it is as good as aducanumab, we still won’t know if that drug actually helps patients. While real-world evidence can play an important role in supplementing clinical trial data, there are significant limitations in establishing a drug’s overall safety and effectiveness profile based on observational real-world evidence: that’s why we conduct clinical trials and that’s why we have an FDA.

Meet the experts

Robert Howard| Professor of Old Age Psychiatry, University College London (UK)aducanumab

Robert Howard is Professor of Old Age Psychiatry at University College London (UK) and Honorary Consultant Psychiatrist at Camden and Islington NHS Trust (London, UK). Much of his research involves the conduct of independent clinical trials in mental health and dementia.

aducanumab

Mark Dallas | Associate Professor in Cellular Neuroscience, School of Pharmacy at the University of Reading (UK)

Dr Mark Dallas is an Associate Professor in Cellular Neuroscience in the School of Pharmacy at the University of Reading (UK). His research investigates the regulation of ion channels and transporters; he has an interest in glial cells within the central nervous system. This has opened an exciting area of research pointing to their use as therapeutic targets to tackle brain disease.

By furthering our understanding of non-neuronal cells he hopes to provide much needed therapeutic strategies for the treatment of Alzheimer’s disease. His work has generously been funded by Alzheimer’s Research UK, Alzheimer’s Association, The Physiological Society and The Royal Society. He holds numerous positions within the scientific community including the Academic Coordinator for the Alzheimer’s Research UK Thames Valley Network, Editor for the British Journal of Pharmacology and Associate Editor for Physiological Reports.

David Whitrap | Vice President of Communications and Outreach at the Institute for Clinical and Economic Review (ICER; MA, USA)aducanumab

David Whitrap is the Vice President of Communications and Outreach at the Institute for Clinical and Economic Review (ICER; MA, USA), helping to raise nationwide awareness of ICER’s value assessments and highlight opportunities for organizations throughout the US health system to deliver broad patient access to sustainable, high-value care.

Prior to joining ICER in 2017, Whitrap led external communications for both a commercial biotech company and a large pharmacy benefit manager, with these cross-industry experiences equipping Whitrap with an unusually broad view of the tensions related to US drug pricing, reimbursement throughout the pharmaceutical supply chain and incentives for biomedical innovation.

Disclaimers

David Whitrap is part of the senior management of the Institute for Clinical and Economic Review (ICER). He has no investment holdings in any pharmaceutical or US payer company. ICER’s drug assessments are funded exclusively by nonprofit foundations.

Life science companies and commercial payers participate in ICER’s Policy Leadership Forum, and their dues contribute to ICER’s annual Policy Summit, which convenes leaders from both industries to discuss broad initiatives that could help deliver fair pricing and fair access across the US pharmaceutical supply chain. In total, contributions from ICER’s Policy Leadership Forum represent approximately 20% of ICER’s total annual revenue, with slightly more funding from life sciences organizations (including Biogen) than payer organizations.

The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of Neuro Central or Future Science Group.